The NU SCOR explores the overarching hypothesis that genetic variation resulting in hyperandrogenemia produces the phenotypic features of the polycystic ovary syndrome (PCOS) by androgen programming in utero as well as by ongoing androgen actions at critical developmental periods and in the adult. We have found sex-specific metabolic phenotypes in PCOS families, mapped several PCOS susceptibility genes, developed animal models of androgen programming and discovered that androgen-mediated estrogen resistance is an important mechanism for these androgen actions. It is clear that the genes for PCOS so far identified do not explain the high heritability of this disorder. We will investigate te mechanisms for this deficit in heritability as well as the molecular mechanisms by which estrogen resistance can produce obesity and metabolic abnormalities in PCOS. Our strategy for achieving the SCOR objectives is to directly investigate the genetic, epigenetic and hormonal determinants PCOS in three highly interactive, synergistic and interdisciplinary projects: Projects I and II are clinical research projects and Projects III will utilize a novel non-human primate model. Although each project is discrete, the proposed SCOR as a whole will continue to comprehensively investigate novel mechanisms for the pathogenesis of PCOS. Project I will test the hypothesis that rare genetic variants will account for much of the deficit in heritabilityof PCOS. We predict that we will identify rare variants in pathways implicated in the pathogenesis of PCOS in mapping of common variants, such as TGF signaling, Wnt signaling, insulin signaling, gonadotropin action and extracellular matrix, as well as rare variants in genes in novel pathways. Project II will test the hypothesis that a significant component of the heritability of PCOS is due to epigenetic changes including variation in methylation patterns, that these changes in methylation patterns correlate with changes in expression patterns, and that these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. Project III will develop a novel non-human primate (marmoset) model of diet-induced obesity to test the hypothesis that androgenic programming of metabolic features of PCOS is mediated by induction of resistance to the actions of estradiol in target hypothalamic neurons that modulate energy homeostasis. These studies are extremely innovative, highly synergistic and likely to have a major impact on the field through elucidating the pathogenesis of PCOS and its metabolic phenotypes.